20-56399081-T-C

Position:

• chr20-56399081-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001324.3(CSTF1):​c.760T>C​(p.Ser254Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CSTF1 NM_001324.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.60

Genes affected

CSTF1 (HGNC:2483): (cleavage stimulation factor subunit 1) This gene encodes one of three subunits which combine to form cleavage stimulation factor (CSTF). CSTF is involved in the polyadenylation and 3'end cleavage of pre-mRNAs. Similar to mammalian G protein beta subunits, this protein contains transducin-like repeats. Several transcript variants with different 5' UTR, but encoding the same protein, have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.78

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSTF1	NM_001324.3	c.760T>C	p.Ser254Pro	missense_variant	5/6	ENST00000217109.9	NP_001315.1
CSTF1	NM_001033521.2	c.760T>C	p.Ser254Pro	missense_variant	5/6		NP_001028693.1
CSTF1	NM_001033522.2	c.760T>C	p.Ser254Pro	missense_variant	5/6		NP_001028694.1
CSTF1	XM_011528600.2	c.760T>C	p.Ser254Pro	missense_variant	5/6		XP_011526902.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSTF1	ENST00000217109.9	c.760T>C	p.Ser254Pro	missense_variant	5/6	1	NM_001324.3	ENSP00000217109.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 06, 2021

The c.760T>C (p.S254P) alteration is located in exon 5 (coding exon 4) of the CSTF1 gene. This alteration results from a T to C substitution at nucleotide position 760, causing the serine (S) at amino acid position 254 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.083	T;T;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;D;D
M_CAP	Benign	0.046	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	1.8	.;L;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Pathogenic	0.68
Sift	Benign	0.10	T;T;T
Sift4G	Benign	0.29	T;T;T
Polyphen		0.92	.;P;.
Vest4		0.76
MutPred		0.46		Gain of catalytic residue at S254 (P = 0.0085);Gain of catalytic residue at S254 (P = 0.0085);Gain of catalytic residue at S254 (P = 0.0085);
MVP		0.80
MPC		1.8
ClinPred		0.91	D
GERP RS		5.6
Varity_R		0.93
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-54974137;